Implantable drug delivery devices have been known in the art. The device is surgically implanted in the body of a human or veterinary patient and the drug is released in an efficacious manner. Such implantable drug delivery systems are particularly useful for delivering drugs at sustained rates over extended periods of time. Examples of drug delivery implants of this type include Norplant®, Lupron Depot®, and Gliadel Wafer®.
In the art-known implantable drug delivery systems the active ingredient is embedded in a matrix material that is shaped in a cylindrical form of sufficient small size to allow subcutaneous implantation via a hollow needle. A disadvantage associated with such delivery systems is that there is a lag time between implantation and delivery of the drug because the bodily fluids have to penetrate the implant and start decomposing the polymeric matrix. This also often leads to irregularities in the release pattern.
Moreover, none such system has been designed to deliver two or more drugs simultaneously. The utility of an implantable drug delivery system would be increased dramatically when this would be made available. Oftentimes a disease state is more efficaciously addressed when treatment includes two or more active agents that can act together in a more comprehensive, synergistic, or more complimentary fashion. An example of this would be the treatment or prevention of infection where members of two different classes of anti-biotics are released from a single depot system. The activity of each anti-biotic targets different bacterial strains and in this fashion provides for a more comprehensive therapy. Another example of utility would be in the delivery of pain drugs. The sustained release of pain medication can provide for long pain-free periods of time for the patient, which is a significant improvement over the peaks and valleys plasma concentrations of the drug inherent in oral therapy. However, the sustained release of multiple pain drugs that have separate mechanisms of action can result in significantly enhanced pain management.
An even more compelling example for a multi-drug depot can be found in the treatment of infectious diseases, for example HIV (Human Immunodeficiency Virus) and HBV (Hepatitis B Virus). Standard therapy for HIV requires a “cocktail” of at least three drugs. Sustained release therapy for HIV can significantly contribute to therapy compliance (reducing pill burden) and reduce the risk of development of resistance to therapeutic actives. The value for this therapy would increase further if the implantable sustained release formulation contained all the components of the drug cocktail rather than have one sustained release and the others remain as an oral therapy. Other infectious diseases that would benefit from this type of therapy are malaria, flu, TB, and Hepatitis C. A multi-drug depot could also be used in a pre-exposure setting for high risk populations, for instance pre-exposure prophylaxis for HIV infection.
De-coupling the formulation of the two actives into separate processes can substantially improve stability, increase the drug loading of each, and introduces compositionally flexibility where one drug can be formulated to release faster or slower or one drug is increased or decreased in dosage depending on the status of the patient.
The ability to remove the device after implantation is important since many of the drugs used in the sustained release applications are potent and can cause severe even life-threatening reactions. Even compressing the microparticles or pellets together into one unit as described in US 2001/0026804 does not guarantee that the device is removable since once the device is in contact with physiological medium the pellets or microparticles will soon separate from one another making it impossible to completely remove.
US2004/0082937 describes an implantable device for the controlled release of a hormone. The device comprises a substrate with a plurality of reservoirs that each contain a release system that is electrically controllable. US2006/0269475 describes a polymer multi-layer structure having a predetermined micro-fabricated special pattern comprising predetermined reservoirs and channels containing the drug. The polymer multi-layer structure is biodegradable but has a longer lifetime than the duration of the therapy that is delivered. The geometrical pattern of the polymer structure controls the delivery of the therapy while persisting during delivery of the therapy. The device is prepared in layers that are fused together at elevated temperature, which can cause significant warping of the reservoir shape leading to significant changes in the overall loading of the drug in the device or release rate of the drug. Moreover, this void or channel approach to loading the device with the drug has a limited capacity for the drug.